A huge investment is being made to develop treatments to restore or provide light sensitivity to the retinas of the blind. Technological advancements in several areas including stem cells, gene therapy, and retinal prostheses show great promise; however, understanding of the basic circuitry for daylight vision lags behind technology to restore light sensitivity. Exciting technological advances reinvigorate the need to understand the circuitry of visual pathways in order to identify the best light-sensitivity-restoring therapeutic strategies and the most effective implementations of them. A complete understanding of the details of the circuitry for processing visual information will bring a wealth of opportunities for developing sophisticated strategies for treating blinding vision disorders. This application focuses on a unique sub system within the primate visual system where there are exceptional opportunities to discover the workings of neural circuitry responsible for specific percepts. It is widely accepted that S-cone input to S-cone bipolar cells and in turn to small bistratified ganglion cells--the so called S-ON/koniocellular pathway-- is the important circuit for blue-yellow color vision; however, the fact that the spectral response properties of small bistratified ganglion cells measured physiologically do not match those of the blue-yellow opponent channel measured perceptually is an unresolved problem for the idea that the small bistratified ganglion is the biological substrate blue perception. There is less information about retinal S-OFF ganglion cells. For the only S-OFF ganglion cells that have been characterized anatomically and physiologically in primate, bath application of the ON-pathway blocker 2-amino- 4-phosphonobutyric acid (AP-4) completely blocks the S-OFF light response, suggesting that both ON and OFF S-cone signals are transmitted to the inner retina via the ON S-cone bipolar cell and that a sign inversion of the ON signal in the inner retinal circuitry is critical for generating the S-OFF response. Thus, in much the same way that rod bipolar cells provide the substrate for both ON and OFF ganglion cell responses, the ON S- cone bipolar cells appear to provide the first stage for a complete S-cone system with both ON and OFF components. Gene mutations in humans have been discovered that completely interrupt the direct transmission of signals between S-cones and the S-cone bipolar cells. These patients offer an unprecedented opportunity to study the role of the S-ON/S-OFF/koniocellular pathways in perception. Specific Aim 1: To study the role of the S-ON/S-OFF/koniocellular pathways in perception through the study of human patients with mutations that block them, using the electroretinogram, functional magnetic resonance imaging and visual psychophysics. Specific Aim 2: To isolate and study specific components of chromatic pathways in animal models using electrophysiology, physiology, and functional magnetic resonance imaging to explore how higher levels of visual processing extract usable information from the light sensitive photoreceptors. PUBLIC HEALTH RELEVANCE: Technological advancements in stem cells, gene therapy, and retinal prostheses show great promise for restoring or providing new light sensitivity to retinas of the blind; however, understanding of the basic circuitry for daylight vision lags behind the technology to provide light sensitivity. Exciting technological advances reinvigorate the need to understand the circuitry of visual pathways in order to identify the best therapeutic strategies and the most effective implementations of them. A complete understanding of the details of the circuitry for processing visual information will bring a wealth of opportunities for developing sophisticated strategies for treating blinding vision disorders. The major objective of this grant is to provide a new understanding of the circuitry responsible for a specific visual capacity--blue-yellow color vision.